Dihalomethano-steroids

ABSTRACT

The compounds are estratriene derivatives containing a 6,7dihalomethano function. The compounds are useful as hypocholesteremics.

United States Patent 72] lnventor Eugene E. Galantay Morristown, NJ.

[21 1 App]. No. 828,739

[22] Filed May 28, 1969 [45] Patented Nov. 23, 1971 [73 Assignee Sandoz-Wander, Inc.

Hanover, NJ.

[54] DlHALOMETHANO-STEROIDS 12 Claims, No Drawings [52] US. Cl ..260/239.55, 260/397.4, 260/397.5, 260/999 Primary Examiner-Henry A. French AnomeysGerald D. Sharkin, Frederick H. Weinfeldt,

Robert 8. Honor, Walter F. Jewell and Richard E. Vila ABSTRACT: The compounds are estratriene derivatives containing a 6,7-dihalomethano function. The compounds are useful as hypocholsteremics.

DIHALOMETHANO-STEROIDS This invention relates to steroidal compounds and more particularly to steroidal compounds with a l,3,5(lO)-estratriene skeleton and containing the 6,7-dihalomethano func- 5 tion.

The compounds of this invention may conveniently be represented by the formula 1:

wherein R is a hydrogen atom, lower alkyl or lower alkanoyl;

R is alkyl having from one to three carbon atoms; R is oxo (=0); ethylenedioxy, i.e. O-CH CH O-,

wherein R is a hydrogen atom, or lower alkanoyl; and

wherein R is as defined above and the substituents R and R have the same definitions as R and R respectively, except that any hydroxylic H- atom is replaced by a protective group, with a dihalocarbene source (compound Ill). Preferred dihalocarbene sources are compounds lila:

wherein X is as defined above.

In the above definition the term protective group signifies a group which is conventionally used to protect or mask a hydroxy function and is removable by acid cleavage, e.g., at pH of from about 7 to 1.5. The function of a protective group is to prevent any hydroxy functions from being affected during said reaction. The particular protective group employed is not critical, provided that it serves to perform the protecting function and is removable as described above, as will be appreciated by one skilled in the art. Preferred protective groups are tetrahydropyran-2-yl or tetrahydrofuran-Z-yl moieties.

The reaction of compounds II and I]! may be carried out by heating the reactants, e.g., at temperatures of from about 70 to 160 C. in an inert organic solvent, e.g., benzene, toluene, cyclohexane, or diglyme. Preferred temperatures are from about to l00 C.

Compounds ll and III are either known and may be prepared as described in the literature, or where not known may be prepared by procedures analogous to those described in the literature.

The compounds I, and protected forms thereof, may be regarded as including the following classes of compounds, depending on the 3-substituent on the A ring:

[ when R OH;

Further subclasses of each class occur due to variations at the l7-position of the D-ring;

R 0 Sub-class 1-when R is and 0 ji a 7cm? L qifi hy rsi ya.

The above-mentioned subclasses l and 2 are further divisible into other types;

I R a hydrogen atom;

1 R Y, as defined above;

I R acyl, as defined above;

2,, R 15 ll ;end

2 R" is ethylenedioxy.

Accordingly, a compound 1,, would be a compound I having protected hydroxy groups at both positions 3 and l 713. A compound I would be a compound l having lower alkanoyloxy groups at both positions -3 and l 73.

Compounds l of the different classes and types are to a certain degree interconvertable. For example, compounds have protected groups may be converted to their corresponding hydroxy-containing analogues. Conversely, compounds I having hydroxy functions may be converted to a protected forms, e.g., to the tetrahydrofuranyl ether.

A compound I wherein R is ethylenedioxy may be converted to its corresponding compound I wherein R is oxy, i.e. the R and the l7 carbon atom together form a carbonyl unit which compound may be reduced to a hydroxy function.

Furthermore, compounds containing hydroxy functions may be acylated to their corresponding alkanoyloxy-contaim ing analogs.

The above-described interconversion of a compound I of one class or type to that particular class or type desired is a convenient alternative to first preparing a compound ll of the appropriate class or type and then reacting it with a compound II] to directly obtain the desired class or type of compound I. Accordingly, the interconversion reactions described below while directed particularly to compounds I, are also applicable to interconversions of appropriate compounds ll.

As will be appreciated by those skilled in the art, reactions at the A and D rings do not occur strictly independently. Reaction conditions applied to a compound may cause reactions at more than one reactive site. Such possibilities should be taken into account when carrying out intercoversion reactions. As is described below with respect to the individual reactions, the A ring is aromatic in nature, while the D ring is cycloaliphatic in nature. Hence, reactants and reaction conditions may be selected whereby a reaction occurs predominently at a single site, to obtain a desire product in optimum yield.

Reactions at the A ring:

l Step d l Step a Reactions at the D ring:

The interconversion" steps may be characterized as follows:

Steps c, d and d are ether cleavages;

Steps 0 and a are acylations; and

Step r is a reduction.

These process steps are described below.

The splittingofi of the protecting group in process steps c, d and 1 d may be efiected by the acid conditions usually employed for the splitting off of the protective groups, e.g., by using p-toluenesulphonic acid hydrate in methanol, ethanol or benzene solution.

The acylation of process steps a and a may be effected by processes known per se for the acylation of steroid alcohols. With respect to compounds of class I, having a plurality of OH groups, i.e. both R and R are hydrogen atoms, it will be noted that, an OH group at the 3-position is phenolic and an OH group at the l7B-position is tertiary. As one skilled in the art will be aware, the ease of acylation is phenolic tertiary and the ease of resaponification is clearly phenolic tertia- LII ry. Accordingly, acylating agents and the stringency of acylating conditions can be chosen depending on the degree of acylation required employing conventional techniques. Suitable acylating agents for the 3-position include acids, acyl halides and acid anhydrides of formulas acyl-OH, acyl-Hal and (acyl),0, respectively, wherein acyl is as defined above, and Hal signifies bromine or chlorine, and mixtures thereof. Where the desired acyl moiety is acetyl, a preferred acylating agent is acetic anhydride. ln carrying out the acylation, inert solvent may be employed or excess acylating agent may serve as solvent. An acid-binding agent, e.g., pyridine, is preferably used. Preferred temperatures vary between l0 and 50 C. For acylation of both position, more stringent conditions may be used, characterized by the presence of a strongly acidic catalyst, e.g., p-toluenesulphonic acid, perchloric acid and the like. If such catalysts are used, in addition to the above-listed acylating agents, enol acylates, preferably esters of isopropenyl alcohol," e.g., isopropenyl acetate, may also be employed. The considerations involved are well within the scope of one skilled in the art. Hence, one skilled in the art can use such knowledge to obtain the desired combination of free OH and acylated positions.

The reduction in process step r may be carried out by any reducing agent which will selectively reduce the l7-keto group. The reaction may, for example, be carried out with a metal hydride, e.g., lithium tri-t-butoxyaluminium hydride or sodium borohydride in an inert solvent, e.g., diethyl ether, diglyme, benzene, ethanol, methylene chloride or a mixture thereof. The reaction may be carried out at a low temperature, for example at a temperature of from about 50 to +1 0 C. The reaction product may be worked up to yield the corresponding compound I, wherein R a hydrogen atom, by treatment with an aqueous base, e.g., dilute sodium hydroxide.

The hydrogen atoms at the six and seven carbon atoms of a compound I may either be both a or both B. Hence, compounds I exist as isomeric forms. The various isomeric forms of compounds I are included within the contemplation of this invention. Where desired the isomeric forms of a particular compound I may be separated by known means, e.g., by fractional crystallization or chromatography.

The compounds of formula (I) are useful because they possess pharmacological properties in mammals. In particular these compounds are useful as hypocholesteremics as indicated by activity in sodium hexobarbital anesthetized rat tested by extracting serum or plasma with isopropanol and noting the cholesterol content. For such usage, the compounds may be administered orally as such or admixedwith conventional pharmaceutical carriers or administered orally in such forms as tablets, dispersible powders, granules, capsules, syrups and elixirs. Such compositions may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more conventional adjuvants, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide an elegant and palatable preparation. Tablets may contain the active ingredient in admixture with conventional pharmaceutical excipients, e.g., inert diluents, such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, e.g., starch and alginic acid, binding agents, e.g., starch, gelatin and acacia, and lubricating agents, e.g., magnesium stearate, stearic acid and talc. The tablets may be uncoated or coated by known techniques to delay disintegration and adsorption in the gastro-intestinal tract and thereby provide a sustained action over a longer period. Similarly, suspensions, syrups and elixirs may contain the active ingredient in admixture with any of the conventional excipients utilized for the preparation of such compositions, e.g., suspending agents (methyl-cellulose, tragacanth and sodium alginate), wetting agents (lecithin, polyoxyethylene stearate and polyoxyethylene sorbitan monooleate) and preservatives (ethyl-p-hydroxybenzoate). Capsules may contain the active ingredient alone or admixed with an inert solid diluent, e.g., calcium carbonate, calcium phosphate and kaolin. Compositions comprising a compound I and a solid carrier or diluent are preferred.

The dosage of active ingredient employed for the alleviation of hypercholesteremia may vary depending on the particular compound employed and the severity of the condition being treated. in general, satisfactory results are obtained when these compounds are administered at a daily dosage of from about 0.5 milligrams to about 50 milligrams per kilogram of animal body weight. This daily dosage is preferably given in divided doses and administered 2-4 times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 50-2000 mg., and dosage forms suitable for internal use comprise from about 12.5 milligrams to about 500 milligrams of active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier or diluent. The preferred pharmaceutical compositions from the standpoint of preparation and ease of administration are solid compositions, particularly hard-filled capsules and tablets containing from 25 milligrams to about 250 milligrams of the active ingredient.

The following examples are provided as illustrative of the present invention. However, it is to be understood that the examples are for the purposes of illustration only and are not intended as in any way limiting the scope of the invention. In the examples all temperatures are Centigrade and room temperature is 25, unless indicated otherwise.

EXAMPLE I 6,7-Dibromomethylene l 7-ethylenedioxy-3-methoxyestral,3,5( l0)-triene O o l OM CHsO Br Br A mixture of 9.255 g. of l7-ethylenedioxy-S-methoxyestral,3,5( l0),6-tetraene, 16.7 g. of phenyl-tribromomethyl mercury and 285 ml. of cyclohexane is heated under reflux for 18 hours. After cooling, 1L0 g. of phenylmercuric bromide is removed by filtration and the filtrate is evaporated to dryness to yellow gum. Latter, upon trituration with ether, crystallizes to give the higher melting isomer of the title product,m.p. l99-200, [a] =-80.4 (c=l CHCL The lower melting stereoisomer of the title product is iso lated by column chromatography (silica gel H, CHCL /Benzene; l:3 system eluent) of the residue obtained on evaporation of the ethereal mother liquor; and crystallization from ethanol, m.p. l85"l 88, [a],,=+0.7 (C=l C HCl EXAMPLE 2 6,7-Dibromomethylene-3methoxyestral .3,5( l0)-trienl 7- one 248 mg. of 3-methoxyestra-1,3,5( l0)-6-tetraene-l7-one is reacted with 490 mg. of phenyl-tribromomethyl mercury as described in example i. Chromatographic purification and recrystallization from ethanol yields the title product, m.p. 19l-l93[a],;=+3.07 (C=l, CHCI EXAMPLE 2a 6,7-Dibromomethylene-3-methoxyestra-l ,3,5( l0)-trien-l 7- one (Alternative method) 800 mg. of 6,7-dibromomethylene-l7-ethylenedioxy-3- methoxyestra-l,3,5(l0)-triene higher melting isomer, 9.4 ml. of ethanol and 94 mg. of p-toluenesulfuric acid hydrate is refluxed for 15 hours. l5 ml. water is added to the reaction mixture, then the reaction mixture is neutralized by the addition of aqueous sodium bicarbonate solution. The title product is then extracted with chlorofonn. The solvent is then evaporated under vacuum to obtain a residue, which on crystallization from ethanol gives the title product, m.p. l9l-l93.

EXAMPLE 3 6,7-dichloromethylene-3-methoxyestra-l ,3,5( 10 )-trienl 7- one CHQO

A mixture of 649.7 mg. of l7-ethylenedioxy-3-methoxyestra-l ,3,5( lO),6-tetraene and H724 g. of phenylbromodichloromethyl-mercury in 20 ml. of cyclohexane is refluxed for 1 hour. After cooling, phenylmercuric bromide is filtered off and the filtrate evaporated under vacuum to obtain a residue. The residue is refluxed 3 hours, in ethanol solution (20 ml.) with 0.50 g. of p-toluenesulfonic acid hydrate, then water is added and the title product extracted with chloroform. On trituration with petroleum ether followed by methanol, the title product crystallizes; m.p. l78-l82.

EXAMPLE 4 3,17B-diacetoxy-6,7-dibromomethylene estra-l ,3,5( 10)- trienc H3O OCOOH;

CH3COO Br Br A mixture of 300 mg. of 3,17fl-diacetoxyestra-l,3,5( l),6- tetraene and 944 mg. of phenyl-tribromomethyl mercury in 3 ml. of absolute benzene is heated at 80 for 2 hours. Phenylmercuric bromide is filtered off and the benzene filtrate is evaporated under vacuum to obtain a residue. The residue is purified on chromatoplates (silica gel H, CHCI, system). The title product, m.p. 87, is obtained by elution of the band, R, about 0.3, with ethyl acetate and high vacuum distillation (l20/.00l mm.).

EXAMPLE 6,7-Dibromomethylene-3 l 7B-dihydroxyestral ,3 ,5( l0 triene H3O OH Br Br The bis-tetrahydropyran-Z-yl ether of 3.17/3-dihydroxyestra-l ,3,5( l0),6-tetraene is reacted under the conditions described in example 4 to obtain the bis-tetrahydropyranlZ-yl ether of 6,7-dibromomethylene-3 ,l 7fldihydroxyestral,3,5(l0)-triene. 300 mg. of the thus-obtained ether compound is dissolved in 5 ml. of methanol, 80 mg. of ptoluenesulfonic acid hydrate is added and the mixture kept at 25 for 18 hours. Water is then added to the reaction mixture, which is then extracted with chloroform. The chloroform extracts are then water-washed, dried over anhydrous sodium sulfate, and then evaporated, under vacuum, to obtain 6,7- dibromomethylene-3J 7B-dihydroxyestral ,3,5( l0 )-triene, as

a solid.

EXAMPLE 6 6,7-dibromomethylene-3-methoxyestral .3,5( l0)-trienl 7B- 01 EC OH OHgO Br Br 6,7-Dibromomethylene-3-methoxyestral .3,5( l0)-trienl7-one (obtainable as described in example 2) (509 mg.) in ml. of ethanolmethylene chloride l:l is treated at 0. with l8l mg. of sodium borohydride. After 45 minutes, water is added and the methylene chloride layer worked up to give the title product: m.p. l70-l 73.

What is claimed is:

l. A compound of the formula:

wherein R is a hydrogen atom, or lower alkanoyl having from two to four carbon atoms; and X is a halogen having an atomic weight of from 35 to with the proviso that the hydrogen atoms at positions 6 and 7 are either both a or both B. y 2. A compound of claim 1 wherein R is a hydrogen atom. 3. The compound of claim 2 which is 6,7- dibromomethylene-3 l 7B-dihydroxy-l ,3 .5( l0 )-triene.

4. A compound of claim 1 wherein R is lower alkyl. 5. The compound of claim 4 which is 6,7- dibromomethylenel 7-ethylenedioxy-3-methoxyestral,3,5( l0)-triene.

6. The compound of claim 4 which is 6,7- dibromomethylene-3-methoxyestral ,3,5( 10 )-trienl 7-one.

7. The compound of claim 4 which is 6,7- dichloromethylene-3-methoxyestral ,3.5( l0)-trienl 7-one.

8. The compound of claim 4 which is 6.7- dibromomethylene-B-methoxyestra-l ,3.5( l0 )-trienl 7fi-ol. 9. A compound ofclaim 1 wherein R is lower alkanoyl. 10. The compound of claim 9 which is 3, l 7B-diacetoxy-6J- dibromomethylene estral ,3,5( l0)-triene.

l I. A compound of the formula:

wherein R is tetrahydropyran-Z-yl or tetrahydrofuran-Z-yl or lower alkanoyl having from two to four carbon atoms; and 

2. A compound of claim 1 wherein R1 is a hydrogen atom.
 3. The compound of claim 2 which is 6,7-dibromomethylene-3,17 Beta -dihydroxyestra-
 4. A compound of claim 1 wherein R1 is lower alkyl.
 5. The compound of claim 4 which is 6,7-dibromomethylene-17-ethylenedioxy-3-methoxyestra-1,3,5(10)-triene.
 6. The compound of claim 4 which is 6,7-dibromomethylene-3-methoxyestra-1,3,5(10)-trien-17-one.
 7. The compound of claim 4 which is 6,7-dichloromethylene-3-methoxyestra-1,3,5(10)-trien-17-one.
 8. The compound of claim 4 which is 6,7-dibromomethylene-3-methoxyestra-1,3,5(10)-trien-17 Beta -ol.
 9. A compound of claim 1 wherein R1 is lower alkanoyl.
 10. The compound of claim 9 which is 3,17 Beta -diacetoxy-6,7-dibromomethylene estra-1,3,5(10)-triene.
 11. A compound of the formula:
 12. The compound of claim 11 which is the bis-tetrahydropyranyl-2-ether of 6,7-dibromomethylene-3,17 Beta -dihydroxyestra-1,3, 5(10)-triene. 